Solid dosage form comprising solid dispersion

ABSTRACT

Provided are a solid dosage form comprising a solid dispersion that allows a drug in the preparation to be rapidly dissolved without compromising the solubility of the solid dispersion, and a method for producing the same. More specifically, provided is a solid dosage form comprising a solid dispersion, the dispersion comprising: a poorly soluble drug, a water-soluble polymer and a disintegrant, wherein the disintegrant is low-substituted hydroxypropylcellulose having an average particle size of 10 to 100 μm and a specific surface area measured by BET method of at least 1.0 m 2 /g. Moreover, provided is a method for producing a solid dosage form comprising a solid dispersion, the method comprising steps of: spraying a water-soluble polymer solution in which a poorly soluble drug has been dispersed or dissolved, on a powder of low-substituted hydroxypropylcellulose having an average particle size of 10 to 100 μm and a specific surface area measured by BET method of at least 1.0 m 2 /g and serving as a disintegrant and granulating the resultant; and drying.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims priority to Japanese Patent ApplicationNos. 2006-215401, filed Aug. 8, 2006 and 2006-287859, filed Oct. 23,2006, the disclosures of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a solid dosage form comprising a soliddispersion produced for improving the solubility of a poorly solubledrug and a method for producing the same. In particular, the presentinvention relates to a solid dosage form comprising a solid dispersion,which rapidly can be disintegrated and allow a drug to be dissolved, anda method for producing the same.

2. Description of the Related Art

Poorly soluble drugs have high crystallinity and extremely lowsolubility in water. Thus, bioavailability or internal absorption ofpreparations produced from these drugs is low, and thus there is theproblem that the drug action is insufficient. As a technique for solvingthis problem, a solid dispersion has been developed in which moleculesof a poorly soluble drug are dispersed in a high molecular weightcarrier, such as a cellulose derivative, in an amorphous state.

Conventional solid dispersions are used as preparations in the form ofcapsules containing a solid obtained by spray-drying a cosolvent inwhich a poorly soluble drug and a carrier are dissolved, or in the formof fine granules or granules as they are. However, the form of tablets,which is a commonly solid dosage form, is most preferable becausetablets are easily prescribed and used in a fixed dose, and easilyhandled and used by patients in use.

It is known that in the case of tablets produced from a solid dispersionpowder, the porosity of the tablets is often lowered not only due to areduced specific surface area, but also due to plastic deformation ofamorphous drug molecules during a compression force and strongcompressibility between high molecular weight carrier particles. Thislow porosity leads to slow permeation of water molecules into thetablets in administration, and to slow disintegration of the tablets,and thus the solid dispersion cannot exert its original effect ofimproving the solubility. Furthermore, the viscosity of a water-solublehigh molecular weight substance or enteric high molecular weightsubstance serving as a carrier increases during hydration ordissolution, and thus a type of hydrogel layer is formed on the surfaceof the tablets during dissolution, so that water is further preventedfrom infiltrating.

As means for solving these problems, PCT Application Japanese PhasePublication 2005-517690 has proposed a tablet that contains a soliddispersion powder obtained by spray-drying, a disintegrant, and anexcipient comprising porosigen. Furthermore, Japanese Patent ApplicationUnexamined Publication No. 5-262642/1993 has proposed a powder in whicha water-soluble high molecular weight base, and if necessary, anexcipient and a disintegrant are added to a poorly soluble drug.However, a concentration-enhancing polymer and a water-soluble highmolecular weight base, serving as carriers, are added in large amounts,and thus the drug release from the preparation is poor, so that thedissolution speed tends to be lowered. Furthermore, in the case of asolid dispersion powder obtained by spray-drying as in PCT ApplicationJapanese Phase Publication No. 2005-517690, it is necessary that afterthe solid dispersion powder is mixed with the other ingredients, themixture is compressed and pulverized for formation of a granulatedpowder for tableting. The particle size of the solid dispersion powderprepared by spray-drying in this manner is small, and thus when it issimply mixed with an excipient, segregation is caused, so that theingredients become non-uniform in the powder for tableting. Moreover,this process makes the operation complicated, and the solid dispersionmay be recrystallized in compression. Furthermore, the disintegrant isadded after the solid dispersion has been prepared, and thus when thesolid dispersion is aggregated and bonded in the tablet due to highbonding strength of the carrier, aggregation may be formed and dispersedin water during disintegration, lowering the solubility of the drug.

Japanese Patent Application Unexamined Publication No. 2004-67606 hasproposed a tablet using fine granules obtained by: spraying a solutioncontaining itraconazole, which is a poorly soluble drug, a water-solublepolymer, and an enteric polymer, on a mixed powder of an excipient and adisintegrant; and granulating and drying the resultant. However, due toits poor disintegration, it takes as long as 360 minutes for the drug tobe dissolved from the tablet. Thus, the disintegration of the tablet isnot improved.

Hirasawa et al. (Journal of the Pharmaceutical Society of Japan, 124(1), 19-23 (2004)) has proposed a tablet produced from a productobtained by: loading an ethanol dispersion liquid as a binding fluidcontaining nilvadipine, which is a poorly soluble drug, crospovidone,and methylcellulose, into a mixed powder of materials such as lactose,methylcellulose, and low-substituted hydroxypropylcellulose; andagitating and granulating the resultant. However, in the ethanolsolution containing nilvadipine, and crospovidone and methylcellulose,serving as carriers, the components are not dissolved. Thus, it seemsthat the solution functions only as an agent for dispersing and dilutingamorphous nilvadipine, because a co-dissolved state is not obtained. Inorder to disperse amorphous drug molecules in a polymer serving as acarrier, it is necessary to obtain a co-dissolved state in a cosolventin which these components are dissolved. Thus, it seems that the soliddispersion of amorphous nilvadipine described in Journal of thePharmaceutical Society of Japan (124(1), 19-23 (2004)) does not havesufficient solubility. Furthermore, due to the influence of thewater-soluble polymer, the disintegration is suppressed, and thus it maybe difficult to obtain a preparation that can be rapidly dissolved.

SUMMARY OF THE INVENTION

The present invention was completed in view of the above-describedcircumstances, and provides a solid dosage form comprising a soliddispersion, which allows a drug in the preparation to be rapidlydissolved without compromising the solubility of the solid dispersion,and a method for producing the same.

The inventors had conducted an in-depth study in order to solve theabove-described problem and found that when special low-substitutedhydroxypropylcellulose is used as a disintegrant, disintegration is notlowered in tablets obtained by compression a solid dispersion, and asolid dosage form rapidly can be disintegrated and allow a drug to bedissolved. As a result, the present invention has been achieved.

More specifically, the present invention provides a solid dosage formcomprising a solid dispersion, dispersion comprising a poorly solubledrug, a water-soluble polymer and a disintegrant, wherein thedisintegrant is low-substituted hydroxypropylcellulose having an averageparticle size of 10 to 100 μm and a specific surface area measured byBET method of at least 1.0 m²/g and serving as a disintegrant. The soliddosage form comprising the solid dispersion preferably may contain anexcipient. Moreover, the present invention provides a method forproducing a solid dosage form comprising a solid dispersion, the methodcomprising steps of: spraying a water-soluble polymer solution in whicha poorly soluble drug has been dispersed or dissolved, on a powder inwhich low-substituted hydroxypropylcellulose having an average particlesize of 10 to 100 μm and a specific surface area measured by BET methodof at least 1.0 m²/g and serving as a disintegrant; and granulating theresultant and drying.

According to the present invention, a solid dosage form with excellentsolubility is obtained. The solid dosage form in the form of agranulated product has high solubility, while the solid dosage form inthe form of a tablet is disintegrated within 10 minutes afterintroduction to a dissolution medium and can release at least 70% byweight of a poorly soluble drug.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the present invention is described in more detail.

A poorly soluble drug used in the present invention has extremely lowsolubility in water, and poor absorption in ordinary oraladministration. For example, the poorly soluble drug refers to a drugthat is “practically insoluble or insoluble” or “very slightly soluble”as prescribed in the Japanese Pharmacopoeia Fifteenth Edition.“Solubility” of a drug in the Japanese Pharmacopoeia Fifteenth Editionrefers to the degree of dissolution of the drug, powdered in the case ofa solid, within 30 minutes in a solvent at 20±5° C., by shaking for 30seconds each time at 5-minute intervals. If a drug is “practicallyinsoluble or insoluble”, then the amount of a solvent (water, in thisspecification) required for dissolving 1 g or 1 ml of the drug is 10,000ml or more. If a drug is “very slightly soluble”, then the amount of asolvent required for dissolving 1 g or 1 ml of the drug is 1,000 ml ormore and less than 10,000 ml.

Specific examples of the poorly soluble drug used in the presentinvention include, but are not limited to, nifedipine, phenacetin,phenyloin, digitoxin, nilvadipine, diazepam, griseofulvin, andchloramphenicol.

In the present invention, molecules of the poorly soluble drug aredispersed in an amorphous state, and thus a water-soluble polymer isused as a carrier. The water-soluble polymer is a polymer that is “verysoluble (the amount of water required for dissolving 1 g or 1 ml of thedrug is less than 1 ml)”, “freely soluble (the amount of water requiredfor dissolving 1 g or 1 ml of the drug is 1 ml or more and less than 10ml)”, or “soluble (the amount of water required for dissolving 1 g or 1ml of the drug is 10 ml or more and less than 30 ml)” as prescribed inthe Japanese Pharmacopoeia Fifteenth Edition, when the polymer is addedto hot water (70° C. or higher) and the mixture is agitated anddispersed, the amount of the hot water ranging from half to the totalamount required for dissolution, and cold water or ice water in anamount of the balance is added during the agitation in a case where theamount of the hot water used is less than the total amount required.Specific examples thereof include: alkylcellulose such asmethylcellulose; hydroxyalkylcellulose such as hydroxyethylcellulose andhydroxypropylcellulose; hydroxyalkylalkylcellulose such ashydroxyethylmethylcellulose and hydroxypropylmethylcellulose; polyvinylalcohol; and polyvinyl pyrrolidone. Of these,hydroxypropylmethylcellulose is particularly preferable.

The content of the water-soluble polymer is 1 to 75% by weight,preferably 1 to 50% by weight, more preferably 1 to 35% by weight, andparticularly preferably 1 to 20% by weight, with respect to the totalamount of the solid dosage form. If the content of the water-solublepolymer is less than 1% by weight, then it may be difficult to obtain acompletely amorphous state of the poorly soluble drug in the soliddispersion. If the content is more than 75% by weight, then the ratio ofthe water-soluble polymer in the preparation becomes large, which maynot be preferable in that the dose and the size of the preparationbecome large and in that the disintegration is lowered.

The weight ratio of the water-soluble polymer added to the poorlysoluble drug is preferably 1 to 5 when taking the poorly soluble drugas 1. If the ratio of the water-soluble polymer is less than 1, then thepoorly soluble drug in the solid dispersion may not be in a completelyamorphous state. If the ratio is more than 5, then the ratio of thewater-soluble polymer in the preparation becomes large, and thus thesize of the preparation becomes large and the dissolution speed islowered, which may not be suitable for a commonly used preparation.

As a solvent used when preparing the solid dispersion that contains thewater-soluble polymer and the poorly soluble drug, a solvent ispreferable in which the poorly soluble drug is well dissolved and thewater-soluble polymer is also dissolved. Examples thereof include:methanol, ethanol, methylene chloride, and acetone; mixed solventsthereof; and solvent mixed with water. The solvent may be selected asappropriate based on the solubility of the poorly soluble drug and thewater-soluble polymer in the solvent.

The solvent is added in an amount in which the solid concentration ispreferably 3 to 18% by weight, and particularly preferably 3.5 to 12% byweight.

Examples of the excipient used in the present invention include lactose,cornstarch, saccharose, mannite, anhydrous calcium phosphate,crystalline cellulose, and their mixtures. It is particularly preferableto use a mixed powder containing lactose and cornstarch in a weightratio of 7:3.

It should be noted that the content of the excipient is preferably anamount (balance) obtained by excluding the poorly soluble drug, thewater-soluble polymer, and a disintegrant described later.

As the disintegrant of the present invention, low-substitutedhydroxypropylcellulose may be used that has an average particle size of10 to 100 μm and a specific surface area measured by the BET method of1.0 m²/g or more, because it provides granulated products with highflowability and ensures high solubility from the compressionpreparation.

The average particle size of the low-substituted hydroxypropylcelluloseof the present invention may be 10 to 100 μm, and preferablyapproximately 20 to 60 μm. If the average particle size is less than 10μm, then aggregability increases because the hydroxypropylcellulose isin the form of fine powder, and thus the flowability of the powder maybe lowered. If the average particle size is more than 100 μm, thenuniformity with the drug is lowered, and thus the product may benon-uniform. The average particle size can be measured using aHELOS&RODOS (manufactured by Sympatec) for measuring particle sizedistribution with laser diffractometry.

Furthermore, the specific surface area of the low-substitutedhydroxypropylcellulose of the present invention may be 1.0 m²/g or more.The reason for this is that if the specific surface area is less than1.0 m²/g, then high compressibility may not be obtained.

It is known that generally, higher specific surface area of a powderprovides higher compressibility of the powder. The specific surface areaanalysis is a method for obtaining the specific surface area of a samplebased on the amount of molecules adsorbed to the surface of particles ofthe powder at the temperature of liquid nitrogen, the molecules havingadsorption occupying area that has been known. For the specific surfacearea analysis, the BET method can be used that is based on physicaladsorption of inert gas at low temperature and low humidity. In themeasurement, for example, MICROMERITICS GEMINI 2375 (manufactured bySHIMADZU CORPORATION) can be used.

Generally, specific surface area can be increased by reducing averageparticle size. However, as described above, if average particle size istoo small, then the aggregability of a powder increases, and theflowability of the powder may be lowered. In the present invention,using compaction-grinding, a powder is provided that has high specificsurface area although its average particle size is sufficient forsecuring the flowability of the powder.

The low-substituted hydroxypropylcellulose preferably has a bulk densityof 0.30 g/ml or more.

Herein, “bulk density” refers to the bulk density in a loosely filledstate, and is measured by uniformly supplying a sample from above (23cm), through a sieve with 24 mesh according to JIS, to a cylindricalvessel (material: stainless steel) with a diameter of 5.03 cm and aheight 5.03 cm (volume 100 ml), and performing weighing after levelingat the upper surface. These operations are performed using a powdertester (PT-D) manufactured by Hosokawa Micron Corporation.

The low-substituted hydroxypropylcellulose of the present inventionpreferably has an elastic recovery ratio of 7% or less when beingsubjected to compression at a compression force of 50 MPa. Accordingly,a dense molded product can be formed in a compressed state.

The elastic recovery ratio refers to an indicator of the compressibilityof a powder. The elastic recovery ratio can be calculated from thefollowing equation, based on the thickness of a tablet obtained bycompression a powder in a tablet weight of 480 mg and at a compressionforce of 50 MPa, using a flat shape (a tableting tester (manufactured bySANKYO PIO-TECH. CO., Ltd.)) with a flat contact face for a tabletdiameter of 11.3 mm.Elastic recovery ratio={(tablet thickness after 30 seconds−minimumtablet thickness)/(minimum tablet thickness)}×100

Herein, “minimum tablet thickness” refers to the lowest point obtainedwhen the powder is compressed by an upper punch of a flat shape unitwith a fixed lower punch, that is, the thickness obtained when thetablet is compressed to the extent possible. “Tablet thickness after 30seconds” refers to the tablet thickness at 30 seconds after the upperpunch is removed upward.

The swelling properties of the low-substituted hydroxypropylcellulosecan be measured, for example, in the following manner: thelow-substituted hydroxypropylcellulose is molded at a compression forceof 1 t into a tablet having a flat face with a diameter of 15 mm; thetablet is swollen by dropping water thereonto; and the swellingproperties are evaluated as the swollen volume increase ratio and theswollen volume increase rate at that time. When alkali cellulose is usedin which the weight ratio of sodium hydroxide with respect to anhydrouscellulose is 0.1 to 0.3, the swollen volume increase ratio is preferably300% or more, and the swollen volume increase rate is preferably100%/min or more.

The swollen volume increase ratio can be obtained in the followingmanner: the powder is molded at a compression force of 1 t into a tablethaving a flat face with a diameter of 15 mm; a punch with a pipe isattached instead of the upper punch; the tablet is caused to absorbwater for 10 minutes by dropping water through this pipe onto the tabletcontained in a mortar; and the swollen volume increase ratio is obtainedat that time. The water is dropped at a rate of 1 ml/min for 10 minutes.The increase in the volume can be calculated from the followingequation, based on a change in the thickness of the tablet.Swollen volume increase ratio=(difference in tablet thickness betweenbefore and after adding water/tablet thickness before adding water)×100

It should be noted that in the equation above, “difference in tabletthickness between before and after adding water” refers to a valueobtained by subtracting the tablet thickness before adding water fromthe tablet thickness after adding water for 10 minutes.

Furthermore, the swollen volume increase ratio of the low-substitutedhydroxypropylcellulose powder is preferably 300% or more in view ofswelling properties, which are important properties as the disintegrant.If the swollen volume increase ratio is less than 300%, then thedisintegration time of a preparation produced from the powder may belonger.

The swollen volume increase rate refers to an initial swelling ratio at30 seconds after starting the addition of water, when the swollen volumeincrease ratio is measured under the same condition as theabove-described method, and can be calculated from the followingequation.Swollen volume increase rate=(difference in tablet thickness before andafter initially adding water/tablet thickness before addingwater)×100/0.5

In the equation above, “difference in tablet thickness before and afterinitially adding water” refers to a value obtained by subtracting thetablet thickness before adding water from the tablet thickness at 30seconds after starting the addition of water.

The swollen volume increase rate of the low-substitutedhydroxypropylcellulose powder of the present invention is preferably100%/min or more in view of swelling properties, which are importantproperties as the disintegrant. If the swollen volume increase rate isless than 100%/min, then the disintegration time of a preparationproduced from the powder may be longer.

The low-substituted hydroxypropylcellulose of the present invention is apowder having high flowability and preferably having a repose angle of42° or less, the repose angle being one type of indicators of theflowability of a powder. The repose angle refers to an angle formed by ahorizontal plane and a generatrix of a corn that is a deposition formedby dropping the sample onto the plane. For example, using a powdertester PT-D (manufactured by Hosokawa Micron Corporation), the reposeangle can be calculated by allowing the sample to flow from a height of75 mm onto a disc-shaped metal stage having a diameter of 80 mm, until aconstant angle is obtained, and then measuring the angle formed by thedeposited powder and the stage. The smaller this angle is, the betterthe flowability of the powder is.

As described in Japanese Patent Application No. 2006-215401, thelow-substituted hydroxypropylcellulose of the present invention can beobtained in the following manner: an aqueous sodium hydroxide solutionis added and mixed with powdered pulp, and thus alkali cellulose isproduced in which the weight ratio of sodium hydroxide with respect toanhydrous cellulose is 0.1 to 0.3; the alkali cellulose is etherified;the sodium hydroxide is neutralized after performing or withoutperforming a dissolution step; the resultant is washed and dried; andthen the dried product is compaction-ground in a pulverization step.

More specifically, a method for producing a low-substitutedhydroxypropylcellulose powder comprises the steps of: (1) adding andmixing an aqueous sodium hydroxide solution with powdered pulp such thatthe weight ratio of sodium hydroxide with respect to anhydrous celluloseis 0.1 to 0.3 so as to produce alkali cellulose; (2) etherifying theobtained alkali cellulose so as to obtain a crude reaction product; (3)neutralizing the sodium hydroxide contained in the obtained crudereaction product; (4) washing and dehydrating the resultant; (5) dryingthe resultant; and (6) pulverizing by compaction-grinding. Furthermore,a method for producing a low-substituted hydroxypropylcellulose powderthat has a number of moles substituted per anhydrous glucose unit of0.05 to 1.0, that is insoluble in water, and that is swollen byabsorbing water, comprises the steps of: (1) adding and mixing anaqueous sodium hydroxide solution with powdered pulp such that theweight ratio of sodium hydroxide with respect to anhydrous cellulose is0.1 to 0.3 so as to produce alkali cellulose; (2) etherifying theobtained alkali cellulose so as to obtain a crude reaction product; (3)neutralizing the sodium hydroxide contained in the obtained crudereaction product without performing a dissolution step of dissolvingpart or whole of the crude reaction product; (4) washing and dehydratingthe resultant; (5) drying the resultant; and (6) pulverizing bycompaction-grinding. In the wash and dehydration step, the resultant ispreferably washed and dehydrated such that the water content is 65% byweight or less.

First, any pulverization method may be applied for obtaining powderedpulp that is used as a raw material. The average particle size thereofis preferably 60 to 300 μm. It is inefficient from an industrialviewpoint to prepare powdered pulp having an average particle size ofless than 60 μm. If the average particle size is more than 300 μm, thenthe uniformity—with the aqueous sodium hydroxide solution may be poor.

The step of producing alkali cellulose is preferably performed bydropping or spraying the aqueous sodium hydroxide solution to thepowdered pulp and mixing the resultant. At that time, the sodiumhydroxide acts as a catalyst in the etherification. The alkali cellulosemay be produced preferably by using either a method in which mixing isperformed in an internally-agitating type reaction device, and thenetherification is successively performed, or a method in which alkalicellulose prepared in another mixing device is charged into a reactiondevice, and etherification is performed.

Furthermore, it was found that the amount of the sodium hydroxide in thealkali cellulose affects not only the reaction efficiency but also theswelling properties and the compressibility of final products. Theoptimum amount of the sodium hydroxide in the alkali cellulose may be0.1 to 0.3 in the weight ratio of the sodium hydroxide with respect toanhydrous cellulose (referring to the balance obtained by removing waterfrom the pulp). If the amount is less than 0.1, then the swellingproperties, in particular, the volume increase ratio when the product isswollen by absorbing water may be lowered, the disintegration may belowered, and the compressibility also may be lowered. Furthermore, ifthe amount is more than 0.3, then the swollen volume increase ratio andthe swollen volume increase rate when absorbing water (described later)may be lowered, and the compressibility also may be lowered.

The sodium hydroxide is preferably added as an aqueous 20 to 40% byweight solution.

The following etherification step is performed by charging the alkalicellulose into a reaction device, performing nitrogen purge, and thencharging propylene oxide into the reaction device as an etherifyingagent, thereby causing a reaction. The ratio of the propylene oxidecharged is preferably approximately 0.1 to 1.0 mole with respect to 1mole of anhydrous glucose units. The reaction temperature isapproximately 40 to 80° C., and the reaction time is approximately 1 to5 hours.

It should be noted that after the etherification step, a dissolutionstep may be performed, if necessary. The dissolution step is performedby dissolving part or whole of the crude reaction product after theetherification in water or hot water. The amount of water or hot waterused varies depending on the amount of the crude reaction product to bedissolved, but the amount of water for dissolving whole of the crudereaction product is usually 0.5 to 10 in the weight ratio with respectto the low-substituted hydroxypropylcellulose in the crude reactionproduct.

In order to further improve the load in the wash and dehydration stepdescribed later, and the compressibility of low-substituted celluloseether, it is preferable not to perform the dissolution step.

In the following neutralization step, since the sodium hydroxide used asthe catalyst remains in the reaction product, neutralization ispreferably performed by loading the crude reaction product into water orhot water containing acids in an amount equivalent to the sodiumhydroxide. Alternatively, neutralization may be performed by addingwater or hot water containing the equivalent amount of acids to thereaction product.

Examples of the acids that are used herein include mineral acids such ashydrochloric acid, sulfuric acid, and nitric acid, and organic acidssuch as fomic acid and acetic acid.

In the following wash and dehydration step, while washing the obtainedneutralized product preferably using water or hot water, dehydration isperformed by a method preferably selected from centrifugation, suctionfiltration, and pressure filtration, for example. The low-substitutedhydroxypropylcellulose in an obtained dehydrated product cake is in theform of fibers as in the raw material pulp. The dehydrated productobtained after performing the dissolution step has a dehydration ratioof approximately 70 to 90% by weight, although this ratio depends on thenumber of moles substituted. The dehydration ratio of the dehydratedproduct obtained without performing the dissolution step is usually 65%by weight or less, so that the load in the following drying step can bereduced, and the productivity is improved. Furthermore, it isadvantageous in that the steps can be simplified because the dissolutionstep is not included.

Furthermore, in view of the compressibility of the product, when afibrous substance is pulverized, the obtained product has higherspecific surface area and thus higher compressibility.

The drying step of drying the obtained dehydrated product is preferablyperformed using a drier such as a fluidized bed drier or a drum drier at60 to 120° C.

The pulverization step may be performed by compaction-grinding the driedproduct obtained by the above-described method.

For this compaction-grinding, a pulverizer such as a roller mill, a ballmill, a bead mill, or a millstone mill can be used. In a roller mill,with a centrifugal force or gravity load accompanying its rotationalmovement, rollers or balls roll over while compressing/shearing apulverization target on a mill wall. Examples thereof include an IS millmanufactured by Ishikawajima-Harima Heavy Industries Co., Ltd., a VXmill manufactured by Kurimoto, Ltd., and an MS roller mill manufacturedby MASUNO SEISAKUSHO LTD. A ball mill uses, as a milling medium, steelballs, magnetic balls, cobbled stones, or the like. Examples thereofinclude a ball mill manufactured by KURIMOTO TEKKO KK, a tube millmanufactured by Otsuka Iron Works, and a planetary ball millmanufactured by FRITSCH. A bead mill is similar to the ball mill, but isdifferent therefrom in that the diameter of balls used is smaller and inthat acceleration of the balls can be further increased by rotating theinternal portion of the device at high speed. Examples thereof include abead mill manufactured by Ashizawa. A millstone mill can grind a powderby rotating a millstone at narrow clearance at high speed. Examplesthereof include Serendipiter manufactured by MASUKO SANGYO CO., LTD.

The roller mill is particularly preferable because it reduces foreignmetal substances mixed in, requires small installation area, andprovides high productivity.

When fibrous particles serving as a pulverizatoin raw material arerepeatedly compaction-ground, the fibrous and hollow tubular formderived from the raw material pulp is lost, and thus primary particlescan be made smaller, so that the specific surface area is increased.Also, since the fibrous form derived from the raw material pulp is lost,a powder having uniform particle shape can be obtained.

It has been considered that the compressibility of low-substitutedhydroxypropylcellulose produced by conventional impact pulverization isexerted by intertwining of fibrous substances. When fibrous particlesare increased based on this idea for improving the compressibility, theflowability is lowered. However, a low-substitutedhydroxypropylcellulose powder produced by compaction-grinding exhibitssurprisingly high compressibility, although the fibrous form has beenlost due to the compaction-grinding.

Next, preferably, the pulverized product is sieved following the usualmethod, and thus the targeted low-substituted hydroxypropylcellulosepowder can be obtained. The opening of a sieve herein may beapproximately 38 to 180 μm.

The thus obtained low-substituted hydroxypropylcellulose powder has highflowability, excellent compressibility, and excellent swellingproperties, regardless of the fibrous form derived from raw materialpulp. Furthermore, due to its excellent compressibility and excellentdisintegration, the amount of this powder added to a tablet can bereduced, and thus the size of the tablet can be made smaller. Moreover,the compression force in production of the tablet can be made lower,which provides the advantage of being able to reduce physical influencessuch as recrystallization of the solid dispersion during process.

In the present invention, in addition to the low-substitutedhydroxypropylcellulose, for example, carmellose, carmellose sodium,carmellose calcium, croscarmellose sodium, hydroxypropyl starch, sodiumcarboxymethyl starch, crospovidone, and their mixtures can be used.

The content of the disintegrant is preferably 1 to 98% by weight, andmore preferably 1 to 60% by weight, with respect to the total amount ofthe solid dosage form. If the content of the disintegrant is less than1% by weight, then it may be difficult to disintegrate the solid dosageform because the amount of the dinintegrant is small. If the content ismore than 98% by weight, then an effective amount of drug may not becontained.

In the solid dosage form of the present invention, the granulatedproduct refers to a powder and a granule prescribed in the JapanesePharmacopoeia Fifteenth Edition.

In a case where the solid dosage form is in the form of a tablet, alubricant may be added, if necessary. Examples of the lubricant includemagnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc,and stearic acid.

In a case where the lubricant is added, the amount of the lubricantadded is preferably 0.5 to 2% by weight with respect to the total amountof the preparation excluding the lubricant. If the amount of thelubricant added is less than 0.5% by weight, then sufficient lubricativeproperties may not be obtained, so that the preparation adheres to amortar or a punch during tableting. If the amount is more than 2% byweight, then the hardness may decrease and the disintegration may belowered.

Next, a method for producing the solid dosage form comprising the soliddispersion according to the present invention is described.

In a case where the solid dosage form comprising the solid dispersion ofthe present invention is a granulated product, the granulated productmay be obtained preferably in a method comprising steps of: spraying awater-soluble polymer solution in which the poorly soluble drug has beendispersed or dissolved, on a mixed powder of the excipient and thedisintegrant; and granulating the resultant and then drying. Morespecifically, in a state where the mixed powder of the excipient and thedisintegrant may be allowed to flow in a granulating device, thewater-soluble polymer solution prepared in advance in which the poorlysoluble drug has been dispersed or dissolved may be sprayed on the mixedpowder, the resultant may be granulated and dried, and then the particlesize may be regulated.

Examples of the granulating device include a fluidized bed granulatingdevice, a high-speed agitation granulating device, a rolling granulatingdevice, and a dry granulating device. The fluidized bed granulatingdevice is particularly preferable because it does not apply mechanicalshear to the granulated product.

There is no particular limitation on the method for producing the soliddosage form of the solid dispersion of the present invention, exceptthat a low-substituted hydroxypropylcellulose having an average particlesize of 10 to 100 μm, and a specific surface area measured by the BETmethod of 1.0 m²/g or more is used as the disintegrant. For example, thefollowing method can be used.

The water-soluble polymer is completely dissolved in the above-describedsolvent such as ethanol or water, and then the poorly soluble drug isloaded thereinto, and thus the solid dispersion solution is obtained.Herein, it is possible to load ingredients constituting the soliddispersion solution into the solvent at a time, but it is preferable todissolve the water-soluble polymer first in order to achieve thestability of the drug in the finally obtained solid dosage form and toshorten the dissolution time of the poorly soluble drug. There is noparticular limitation on the concentration of the solid dispersionsolution, but the concentration is preferably 400 mPa·s or less, andparticularly preferably 100 mPa·s or less, because the solution is to besprayed.

While the mixture of these various ingredients such as the disintegrantis allowed to flow, for example, in the fluidized bed granulatingdevice, the solid dispersion solution is sprayed thereon, and theresultant is granulated and dried, and thus the granulated product canbe obtained. In the spray/granulation step, the charge air temperatureis preferably 150° C. or lower, and particularly preferably 100° C. orlower, considering a case in which an organic solvent is used.

The discharge air temperature is preferably 30° C. or higher, andparticularly preferably 40° C. or higher. The spray rate is preferably50 g/min or less, and particularly preferably 30 g/min or less. Thespray air pressure is preferably 250 kPa or less, and particularlypreferably 200 kPa or less. Furthermore, after the spraying, in thedrying step performed in order not to leave the solvent in the obtainedgranulated product, the charge air temperature is preferably 150° C. orlower, and particularly preferably 100° C. or lower, and the drying timeis preferably 10 to 60 minutes.

The obtained granulated product can be used as it is. However, theobtained granulated product can be, for example, sieved or pulverizedfor obtaining a solid dosage form having more uniform particle sizedistribution. For example, the particle size may be regulated with asieve with an opening of 500 μm, for example.

On the other hand, in a case where the solid dosage form of the soliddispersion is a tablet, the tablet may be obtained by performingcompression in a tableting machine, using the granulated productobtained by the above-described method as a powder for tableting, andadding a lubricant thereto, if necessary.

For the tableting, for example, a rotary tableting machine, or a singletableting machine may be used. However, there is no limitation to this,and a specially customized tableting machine also may be used. Thecompression force during tableting is 1 to 130 kg/cm², and particularlypreferably 10 to 100 kg/cm².

When the thus obtained granulated product of the solid dispersion isevaluated following “Dissolution Test, Method 2” described in theJapanese Pharmacopoeia Fifteenth Edition, the concentration of the drugdissolved within 5 minutes after administration is 70% or more withrespect to the dose, that is, high solubility is exhibited.

When the obtained tablet of the solid dispersion is evaluated following“Disintegration Test” described in the Japanese Pharmacopoeia FifteenthEdition, the tablet is disintegrated within 10 minutes afteradministration, and when the tablet is evaluated following “DissolutionTest, Method 2” described in the Japanese Pharmacopoeia FifteenthEdition, the concentration of the drug dissolved within 10 minutes afteradministration is 70% or more with respect to the dose, that is, highdisintegration and high solubility are exhibited.

The solid dosage form obtained in the present invention may be coated byknown methods in order to provide taste-masking or odor-masking, to makethe preparation enteric, or to achieve slow release of the preparation.Examples of the coating agent used at that time include: entericpolymers such as cellulose acetate phthalate, methacrylic acid copolymerL, methacrylic acid copolymer LD, methacrylic acid copolymer S,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, and carboxymethylethylcellulose; stomach-solublepolymers such as polyvinyl acetal diethylaminoacetate and aminoalkylmethacrylate copolymer; and the water-soluble polymers described above.

EXAMPLES

Hereinafter, the present invention is specifically described by way ofexamples and comparative examples, but the present invention is notlimited to these examples.

Synthesis Examples 1 to 3

Synthesis Example of the Low-Substituted Hydroxypropylcellulose Powder

First, 806 g of powdered pulp (750 g in an anhydrous state) was chargedinto a 10 L internally-agitating type reaction device, 303 g of 26%sodium hydroxide solution was charged into the reaction device, thenmixing was performed at 45° C. for 30 minutes, and thus alkali cellulosewas obtained in which the weight ratio of sodium hydroxide with respectto anhydrous cellulose was 0.105. Next, nitrogen purge was performed,123 g of propylene oxide (0.164 parts by weight with respect tocellulose) was added to the resultant, then the mixture was reacted at ajacket temperature of 60° C. for 1.5 hours, and thus 1232 g ofhydroxypropylcellulose crude reaction product was obtained in which thenumber of moles substituted with hydroxypropoxyl groups per anhydrousglucose unit was 0.28. The etherification efficiency was 61.4%.

Next, 236 g of 50% by weight acetic acid was added and mixed in the 10 Linternally-agitating type reaction device, thereby performingneutralization. The neutralized product was washed in hot water at 90°C. and dehydrated, using a batch-type centrifuge at a rotational speedof 3000 rpm. The water content of the dehydrated product was 58.2% byweight. The dehydrated product was dried at 80° C. for one whole day andnight in a shelf drier.

The dried product was pulverized using a batch-type planetary ball millP-5 manufactured by FRITSH, at 255 rpm for 60 minutes. The pulverizedproduct was sieved through sieves with openings of 38, 75, and 180 μm,and thus the low-substituted hydroxypropylcellulose powders (Samples 1to 3, respectively) having a hydroxypropoxyl group content of 10.9% byweight were obtained. These powders were evaluated by theabove-described method, in terms of average particle size, specificsurface area, bulk density, repose angle, elastic recovery ratio,compressibility, swollen volume increase ratio, and swollen volumeincrease rate. Table 1 shows the evaluation results.

TABLE 1 evaluation results of powder properties swollen swollen averagespecific flowablity elastic compressibility volume volume particlesurface bulk repose recovery tablet increase inrease size area densityangle ratio hardness ratio rate (μm) (m²/g) (g/mL) (°) (%) (kgf) (%)(%/min) Syn. Ex. 1 24 1.25 0.45 38 3.5 45 302 175 Syn. Ex. 2 42 1.210.42 37 3.8 42 330 190 Syn. Ex. 3 57 1.08 0.41 37 4.5 40 401 200

Examples 1 to 3 and Comparative Examples 1 to 3

Solid dispersion solutions were prepared by dissolving predeterminedamounts (listed in Table 2) of nifedipine andhydroxypropylmethylcellulose (HPMC) (hydroxypropoxyl group 8.7% byweight, methoxyl group 28.8% by weight, 6 mPa·s), in a mixed solventcontaining ethanol and water in a weight ratio of 8:2. Then, in a statewhere a mixture of predetermined amounts (listed in Table 2) oflow-substituted hydroxypropylcellulose (L-HPC), lactose (Pharmatosemanufactured by DMV International), and cornstarch (cornstarch Wmanufactured by NIHON SHOKUHIN KAKO) was allowed to flow in a fluidizedbed granulating device (Multiplex MP-01 manufactured by POWREXCORPORATION), the solid dispersion solutions were sprayed on themixture, the resultants were granulated and dried, the particle size wasregulated with a sieve of 30 mesh (opening 500 μm), and thus granulatedproducts were obtained. The granulating and drying conditions at thattime are as below.

Inlet air temperature: 60° C.,

discharge air temperature: 40° C.;

Spray rate: 10 g/min,

spray air pressure: 200 kPa;

Inlet air temperature in drying step: 75° C.,

drying time: 15 minutes.

Comparative Example 1

A granulated product was produced as in Example 1, except that powdersexcluding the low-substituted hydroxypropylcellulose in Example 1 wereprepared in the composition in Table 2.

Comparative Examples 2 and 3

Granulated products were produced as in Example 1, except thatlow-substituted hydroxypropylcellulose (L-HPC) (hydroxypropoxyl group10.9% by weight, average particle size 44 μm, specific surface area 0.92m²/g, bulk density 0.44 g/ml, repose angle 39°, elastic recovery ratio3.8%, swollen volume change ratio 250%, swollen volume change rate200%/min) was used instead of the low-substituted hydroxypropylcellulosein Example 1.

Table 2 shows results obtained by observing the granulated products ofthe respective formulae, in terms of a flowing state of the granulatedproducts in the granulating step.

In the evaluation of a flowing state, if the flowing state is“Excellent”, then the flowability is particularly good. If the flowingstate is “Good”, then the flowability is good. If the flowing state is“Poor”, then the flowability is comparatively poor, and there areindications that blocking (referring to a state in which powder isretained and does not flow in layers) occurs in layers. If the flowingstate is “Disable”, then the fluid is blocked in layers and cannot flow.

As shown in Table 2, the granulated products in Examples 1 to 3 usingSamples 1 to 3 were excellent in flowability, but the flowability of thegranulated product in Comparative Example 1 or 2 was poorer than thoseof Examples 1 to 3. Furthermore, in Comparative Example 3, theflowability of the granulated powder was lowered during process, andblocking occurred in layers, so that it was impossible to completegranulation.

TABLE 2 composition nifedipine HPMC L-HPC lactose corn starch total (g)(g) (g) (g) (g) (g) flowability Example 1 12 24 96 *1 75.6 32.4 240excellent Example 2 12 24 96 *2 75.6 32.4 240 excellent Example 3 12 2496 *3 75.6 32.4 240 excellent Comp. Ex. 1 12 24 — 142.8 61.2 240 goodComp. Ex. 2 12 24 48 109.2 46.8 240 poor Comp. Ex. 3 12 24 96 75.6 32.4240 not flow *1 L-HPC (Sample 1) of Synthesis Example 1 was used. *2L-HPC (Sample 2) of Synthesis Example 2 was used. *3 L-HPC (Sample 3) ofSynthesis Example 3 was used.

Drug Solubility of Examples 1 to 3 and Comparative Examples 1 and 2

The granulated products obtained in Examples 1 to 3 and ComparativeExamples 1 and 2 were tested in an amount of 1800 mg (containing 90 mgof nifedipine) following Paddle method of Dissolution Test in theJapanese Pharmacopoeia Fifteenth Edition. As the conditions forDissolution Test, the rotational speed was set to 100 rpm, and 900 ml ofwater was used as a test fluid. For the sake of reference, 90 mg ofnifedipine bulk powder was also tested in a similar manner. Table 3shows the results.

All of the granulated products in Examples 1 to 3 exhibited solubilityhigher than that of the granulated products of the comparative examples.On the other hand, the granulated product of Comparative Example 2exhibited solubility improved more than that in a case in which thedisintegrant was not added (Comparative Example 1), but the degree ofthe improvement was smaller than that of the examples. On the contrary,in a case where the amount of the disintegrant was large (ComparativeExample 3), blocking occurred during fluidized bed granulation, and thusit was difficult to perform good granulation.

In the evaluation above, it has been confirmed that the granulatedproducts of the solid dispersions of the present invention allow thedrug to be dissolved rapidly and at high rate.

TABLE 3 dissoluition percentage of drug (%) time (minutes) 0 2 5 10 1520 30 Example 1 0 99.5 100 91.5 79.6 72.8 67.8 Example 2 0 93.2 99.185.8 76.9 71 62.1 Example 3 0 80.6 93.9 89.5 69.5 63.6 54.7 Comp. Ex. 10 46.9 59.8 61.2 59.8 58.2 57 Comp. Ex. 2 0 60.5 68.1 66.6 65.8 64.562.8 Comp. Ex. 3 no measurable becaues granulation was impossiblenifedipine alone 0 0.6 3.4 9.3 10 10.6 11.9

Examples 4 to 6 and Comparative Examples 4 and 5

Using the granulated products prepared in Examples 1 to 3 as powders fortableting, 201 mg of tablets were produced (Examples 4 to 6) by adding0.5% by weight of magnesium stearate as a lubricant to the powders fortableting, mixing the resultants, and processing the mixtures in arotary tableting machine (Vergo manufactured by Kikusui Seisakusho Ltd.)at a molding pressure of 20 kg/cm². As comparative examples, usinggranulated products prepared in Comparative Examples 1 and 2 as powdersfor tableting, tablets were produced (Comparative Examples 4 and 5) asin Example 4. The obtained tablets were tested in terms of hardness anddisintegration. Table 4 shows the results.

The tablets obtained in Examples 4 to 6 exhibited appropriate hardnessand excellent disintegration. On the other hand, in the tablets obtainedin Comparative Examples 4 and 5, appropriate hardness was obtained butthe disintegration time became longer.

TABLE 4 composition per tablet tablet disintegration nifedipine HPMCL-HPC lactose corn starch St-Mg total hardness time (mg) (mg) (mg) (mg)(mg) (mg) (mg) (kgf) (min) Example 4 10 20 80 *1 63 27 1 201 6.2 9.1Example 5 10 20 80 *2 63 27 1 201 6.3 8.9 Example 6 10 20 80 *3 63 27 1201 6.3 7.6 Comp. Ex. 4 10 20 — 119 51 1 201 10.1 24.5 Comp. Ex. 5 10 2080 63 27 1 201 8.4 20 *1 L-HPC of Synthesis Example 1 (Sample 1) wasused. *2 L-HPC of Synthesis Example 2 (Sample 2) was used. *3 L-HPC ofSynthesis Example 3 (Sample 3) was used.

Drug solubility of Examples 4 to 6 and Comparative Examples 4 and 5

Dissolution Test as in Examples 1 to 3 was performed on 1809 mg of thetablets (containing 90 mg of nifedipine) obtained in Examples 4 to 6 andComparative Examples 4 and 5. Furthermore, for the sake of reference, 90mg of nifedipine bulk powder was also tested in a similar manner. Table5 shows the results.

In the tablets obtained in Examples 4 to 6, the dissolution rate was byno means inferior to that from the granulated products. On the otherhand, in the tablet in which the low-substituted hydroxypropylcelluloseserving as the disintegrant was not added (Comparative Example 4) andthe tablet obtained in Comparative Example 5, the solubility was notsubstantially improved.

In the evaluation above, it has been confirmed that the tablets of thesolid dispersions of the present invention have excellentdisintegration, and rapid and high solubility.

TABLE 5 dissolution percentage of drug (%) time (minutes) 0 2 5 10 15 2030 Example 4 0 75.3 78.4 76.9 79.9 79.9 78.4 Example 5 0 71.8 79.2 82.283.7 83.7 85.1 Example 6 0 56.6 81.8 83.2 81.8 83.2 75.8 Comp. Ex. 4 07.5 21.8 42.8 50.3 49.2 48.2 Comp. Ex. 5 0 24.6 43.1 50.2 49.2 48.2 47.7nifedipine alone 0 0.6 3.4 9.3 10 10.6 11.9

Examples 7 to 10

Granulated products were obtained as in Examples 1 to 3, usingpredetermined amounts (listed in Table 6) of nifedipine,hydroxypropylmethylcellulose (HPMC), lactose (Pharmatose manufactured byDMV International), and cornstarch (cornstarch W manufactured by NIHONSHOKUHIN KAKO), in the mixing ratios in Table 6.

Table 6 shows results obtained by observing the granulated products ofthe respective formulae, in terms of a flowing state of the granulatedproducts in the granulating step.

In the evaluation of a flowing state, if the flowing state is“Excellent”, then the flowability is particularly good. If the flowingstate is “Good”, then the flowability is good. Examples 7 to 10exhibited good flowability.

TABLE 6 composition nifedipine HPMC L-HPC *1 lactose corn starch total(g) (g) (g) (g) (g) (g) flowability Example 7 6 12 48 121.8 52.2 240excellent Example 8 6 12 96 88.2 37.8 240 excellent Example 9 12 24 14442 18 240 excellent Example 10 18 36 144 29.4 12.6 240 good *1 L-HPC ofSample 2 was used.

Drug solubility of Examples 7 to 10

The granulated products obtained in Examples 7 to 10 in an amount of1800 mg (containing 90 mg of nifedipine) were evaluated as in Examples 1to 3. Table 7 shows the results.

All of the granulated products obtained in Examples 7 to 10 allowed thedrug to be dissolved rapidly and at high rate.

TABLE 7 dissolution percentage of drug (%) time (minutes) 0 2 5 10 15 2030 Example 7 0 100 100 94.6 82.8 72.5 60.6 Example 8 0 100 100 100 100100 87.2 Example 9 0 99.5 100 91.5 79.6 72.8 67.8 Example 10 0 90.6 93.782.9 72.2 66 61.4

Examples 11 and 12

Using the granulated products prepared in Examples 7 and 8 as powdersfor tableting, tablets were produced (Examples 11 and 12) as in Examples4 to 6 in which 0.51 by weight of magnesium stearate was added as alubricant and mixed with the powders for tableting. The obtained tabletswere tested in terms of hardness and disintegration as in Examples 4 to6. Table 8 shows the results.

The tablets obtained in Examples 11 and 12 exhibited appropriatehardness and excellent disintegration.

TABLE 8 composition tablet disintegration nifedipine HPMC L-HPC* lactosecorn starch St-Mg total hardness time (mg) (mg) (mg) (mg) (mg) (mg) (mg)(kgf) (min) Example11 10 20 20 105 45 1 201 9.1 7.6 Example12 10 20 8063 27 1 201 10.1 6.9 *L-HPC of Sample 2 was used.

Drug solubility of Examples 11 and 12

Dissolution Test from tablets was performed as in Examples 4 to 6, on1890 mg of the tablets (containing 90 mg of nifedipine) obtained inExamples 11 and 12. Table 9 shows the results.

In the tablets obtained in Examples 11 and 12, the dissolution rate ofthe drug was by no means inferior to that from the granulated powders.Furthermore, the solubility was improved by increasing the amount of thedisintegrant added.

In the evaluation above, it has been confirmed that the tablets of thesolid dispersions of the present invention have excellentdisintegration, and rapid and high solubility.

TABLE 9 dissolution percentage of drug (%) time (minutes) 0 2 5 10 15 2030 Example11 0 99.1 100 99.1 88.7 75.4 63.6 Example12 0 75.4 100 100 100100 90.2

1. A solid dosage form comprising a solid dispersion, the dispersioncomprising a poorly soluble drug, a water-soluble polymer and adisintegrant, wherein the disintegrant is compaction-groundlow-substituted hydroxypropylcellulose having an average particle sizeof 10 to 100 μm and a specific surface area measured by BET method of atleast 1.0 m²/g, and wherein said disintegrant is compaction-groundlow-substituted hydroxypropylcellulose having 5 to 16% by weight ofhydroxypropoxyl groups.
 2. The solid dosage form comprising the soliddispersion according to claim 1, wherein said solid dispersion furthercomprises an excipient.
 3. The solid dosage form comprising the soliddispersion according to claim 1, wherein said disintegrant islow-substituted hydroxypropylcellulose having a bulk density of at least0.30 g/ml.
 4. The solid dosage form comprising the solid dispersionaccording to claim 1, wherein said disintegrant is low-substitutedhydroxypropylcellulose having an elastic recovery ratio of not greaterthan 7% when compression at a compression force of 50 MPa.
 5. The soliddosage form comprising the solid dispersion according to claim 1,wherein said disintegrant is low-substituted hydroxypropylcellulosehaving a swollen volume increase ratio of at least 300% and a swollenvolume increase rate of at least 100%/min when absorbing water.
 6. Thesolid dosage form comprising the solid dispersion according to claim 1,wherein said disintegrant is compaction-ground low-substitutedhydroxypropylcellulose having a repose angle of not greater than 42°. 7.The solid dosage form comprising the solid dispersion according to claim1, wherein said water-soluble polymer is selected from the groupconsisting of alkylcellulose, hydroxyalkylcellulose,hydroxyalkylalkylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
 8. The solid dosage form comprising the solid dispersionaccording to claim 2, wherein said disintegrant is compaction-groundlow-substituted hydroxypropylcellulose having a bulk density of at least0.30 g/ml.
 9. The solid dosage form comprising the solid dispersionaccording to claim 2, wherein said disintegrant is compaction-groundlow-substituted hydroxypropylcellulose having an elastic recovery ratioof not greater than 7% when compression at a compression force of 50MPa.
 10. The solid dosage form comprising the solid dispersion accordingto claim 2, wherein said disintegrant is compaction-groundlow-substituted hydroxypropylcellulose having a swollen volume increaseratio of at least 300% and a swollen volume increase rate of at least100%/min when absorbing water.
 11. The solid dosage form comprising thesolid dispersion according to claim 2, wherein said disintegrant iscompaction-ground low-substituted hydroxypropylcellulose having a reposeangle of not greater than 42°.
 12. The solid dosage form comprising thesolid dispersion according to claim 2, wherein said water-solublepolymer is selected from the group consisting of alkylcellulose,hydroxyalkylcellulose, hydroxyalkylalkylcellulose, polyvinyl alcohol,and polyvinyl pyrrolidone.